High-altitude polycythemia (HAPC) is one of the classic chronic mountain sicknesses and has been a serious public health problem in high-altitude regions. Despite numerous studies on HAPC via genomics or transcriptomics approaches, the pathogenesis of HAPC is still unclear. Here, we performed a TMT- based comparative quantitative proteomics analysis to reveal the changes of plasma proteomics profiles between HAPC subjects and healthy controls. Of identified 818 proteins, 7 and 12 proteins were up-regulated and down-accumulated, respectively, compared HAPC patients with healthy controls. GO and KEGG pathway analyses revealed the dysregulated proteins were primarily involved in complement and coagulation cascades, inflammation and immune response. ELISA validation demonstrated that C4A, C6 and CALK were down-regulated, and MASP1 and CNDP1 were up-regulated in HAPC patients. By ROC analysis, combinations of these five proteins (i.e., C4A, C6, CALR, MASP1 and CNDP1) resulted in a high AUC value (0.919; 95% CI, 0.817-961; p < .0001) to diagnose HAPC patients. Moreover, CNDP1 seems to be a robust biomarker for HAPC. This study not only provided a comprehensive dataset on overall proteomics changes in HAPC patients compared with healthy controls, but also indicated that CNDP1 can serve as a strong plasma biomarker of HAPC for the diagnostic and therapeutic potential. Significance: HAPC, one of the classic chronic mountain sicknesses, has been a serious public health problem in high-altitude regions. Despite numerous studies on HAPC via genomics or transcriptomics approaches, the pathogenesis of HAPC is still largely unknown to date. In this study, we addressed this issue by performing TMT-based quantitative analyses of the plasma proteome profiles of HAPC patients and healthy controls. We identified 818 proteins, of which 19 were differentially expressed. Bioinformatics analysis revealed the differentially expressed proteins were mainly involved in complement and coagulation cascades, inflammation and immune response. By ROC analysis, combinations of C4A, C6, CALR, MASP1 and CNDP1 resulted in a high AUC value (0.919, p < .0001) to distinguish HAPC patients from healthy controls. Collectively, the current study provided a comprehensive dataset on overall proteomic changes in HAPC patients for the first time, and it also revealed C4A, C6, CALR, MASP1 and CNDP1 can be served as candidate plasma biomarkers of HAPC for their diagnostic and therapeutic potential.
Background. Living at a high plateau in a very hostile environment and low oxygen levels often leads to the development of high-altitude polycythemia (HAPC) and gastric mucosal lesions caused by high-level reactive oxygen species (ROS). Hypoxia-inducible factor-1A (HIF-1A) helps maintain oxygen homeostasis by promoting the transcription of various genes and can be affected by ROS levels. To evaluate the molecular mechanism by which HAPC causes the gastric mucosal lesions, the expression of HIF-1A was measured in Tibetans with HAPC and in healthy subjects. Ultrastructural, histopathological, and immunohistochemical analyses were performed in the gastric tissues of both groups, and the expression of HIF-1A in the gastric mucosa was detected using qPCR and Western Blot. Results. The microvessel density and average diameter of gastric mucosal vessels were significantly greater in the HAPC patients than in the healthy subjects (p < 0.05). The number of red blood cells in the gastric mucosa was also significantly higher in the HAPC group than in the healthy subjects (p < 0.05). In addition, the density of the mitochondrial vacuoles and endoplasmic reticulum and pathological apoptosis were significantly increased in the gastric cells from HAPC patients compared to those from the healthy subjects. The levels of ROS and HIF-1A in the gastric mucosa were increased in HAPC patients compared to those in controls (p < 0.05). Conclusions. An increased level of HIF-1A was associated with HAPC development in the stomach of Tibetans living at a high altitude. ROS upregulated the levels of HIF-1A. Thus, ROS-mediated HIF-1A signaling transduction may be the mechanism associated with HAPC-induced gastric lesions.
Tibetans adapt to high altitude environments through low blood hemoglobin concentrations. Previous work has identified that CYP17A1 and CYP2E1 genes exhibit evidence of local positive selection for this Tibetan high-altitude adaptation. Nevertheless, despite this apparent genetic advantage, some Tibetans still develop high altitude polycythemia (HAPC) yet the reasons for this remain unknown. We sought to determine if polymorphisms in CYP17A1 and CYP2E1 genes were associated with susceptibility to HAPC in Tibetans at the Qinghai-Tibetan Plateau in China. We enrolled 63 Tibetan HAPC patients and 131 healthy, age- and gender-matched control Tibetans. All subjects are from the Yushu area of Qinghai where the altitude is over 3500 m. Three SNPs of the CYP17A1 including rs3781287, rs11191548 and rs1004467, and four SNPs of CYP2E1 gene, including rs1536836, rs3813865, rs3813867 and rs743535, were genotyped by the Sequenom MassARRAY SNP assays. We discovered that SNP rs1004467 of the CYP17A1 gene and SNP rs3813865 of the CYP2E1 gene were significantly associated with HAPC risk. Furthermore, we identified a positive correlation between these two SNPs and plasma hemoglobin levels. Thus, taken together, our study is the first to our knowledge to show that polymorphisms in the rs1004467 SNP of CYP17A1 and rs3813865 SNP of CYP2E1 correlate with susceptibility to HAPC (C) 2015 Elsevier B.V. All rights reserved.
Background: High-altitude polycythemia (HAPC) is a chronic high-altitude disease that can lead to an increase in the production of red blood cells in the people who live in the plateau, a hypoxia environment, for a long time. The most frequent symptoms of HAPC include headache, dizziness, breathlessness, sleep disorders, and dilation of veins. Although chronic hypoxia is the main cause of HAPC, the fundamental pathophysiologic process and related molecular mechanisms responsible for its development remain largely unclear yet. Aim/methods: This study aimed to explore the related hereditary factors of HAPC in the Chinese Han and Tibetan populations. A total of 140 patients (70 Han and 70 Tibetan) with HAPC and 60 healthy control subjects (30 Han and 30 Tibetan) were recruited for a case-control association study. To explore the genetic basis of HAPC, we investigated the association between HAPC and both phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit delta gene (PIK3CD) and collagen type IV a3 chain gene (COL4A3) in Chinese Han and Tibetan populations. Results/conclusion: Using the unconditional logistic regression analysis and the false discovery rate (FDR) calculation, we found that eight SNPs in PIK3CD and one SNP in COL4A3 were associated with HAPC in the Tibetan population. However, in the Han population, we did not find any significant association. Our study suggested that polymorphisms in the PIK3CD and COL4A3 were correlated with susceptibility to HAPC in the Tibetan population.
Objective To investigate the clinical features, treatment and prognosis of high altitude polycythemia mainly manifested as bilateral papilledema. Methods Clinical data of 7 patients with high altitude polycythemia mainly manifested as bilateral papilledema in our hospital from March 2007 to September 2017 were retrospectively analyzed, including clinical manifestations, laboratory results, ophthalmologic examinations, head imaging features, mitochondrial gene detection, treatment and prognosis. Results There were 6 male patients and one female patient, with mean age (44.43 ± 9.05) years old, high altitude residence 7 (4, 13) months, and duration (28.43 ± 10.05) d. All patients were detected with high concentrations of hemoglobin (> 210 g/L), and different degrees of bilateral papilledema after onset. One eye had severe vision impairment [best corrected visual acuity (CVA) was finger counting], and the CVA of other 13 eyes were > 0.10. Visual field defects included enlargement of psychological blind spot (2 eyes), lower altitudinal visual field defect (4 eyes), central scotoma (2 eyes) and diffuse visual field defect (6 eyes). Brain MRI of 7 cases showed dot-like and patchy long T1 and long T2 signals in frontal lobe, parietal lobe and paraventricular region. Optic nerve MRI showed hyperintense signal and slight enhancement in 7 eyes and no abnormality in other 7 eyes. All patients were treated by antiplatelet therapy and microcirculation improvement. Best CVA of all patients were remarkably improved within follow up of 6 months. Conclusions High altitude polycythemia mainly manifested as bilateral papilledema was easily misdiagnosed as other diseases. Moving away from plateau, decreasing hemoglobin, anti-platelet therapy and microcirculation improvement may play an important role in the favorable prognosis. DOI: 10.3969/j.issn.1672-1731.2019.02.008
Because the pathogenesis of high altitude polycythemia (HAPC) is unclear, the aim of the present study was to explore whether abnormal iron metabolism is involved in the pathogenesis of HAPC and the possible cause. We examined the serum levels of iron, total iron binding capacity, soluble transferrin receptor (sTfR), ferritin, and hepcidin as well as erythropoietin (EPO) and inflammation-related cytokines in 20 healthy volunteers at sea level, 36 healthy high-altitude migrants, and 33 patients with HAPC. Mice that were exposed to a simulated hypoxic environment at an altitude of 5,000 m for 4 weeks received exogenous iron or intervention on cytokines, and the iron-related and hematological indices of peripheral blood and bone marrow were detected. The effects of some cytokines on hematopoietic cells were also observed. Iron mobilization and utilization were enhanced in people who had lived at high altitudes for a long time. Notably, both the iron storage in ferritin and the available iron in the blood were elevated in patients with HAPC compared with the healthy high-altitude migrants. The correlation analysis indicated that the decreased hepcidin may have contributed to enhanced iron availability in HAPC, and decreased interleukin (IL)-10 and IL-22 were significantly associated with decreased hepcidin. The results of the animal experiments confirmed that a certain degree of iron redundancy may promote bone marrow erythropoiesis and peripheral red blood cell production in hypoxic mice and that decreased IL-10 and IL-22 stimulated iron mobilization during hypoxia by affecting hepcidin expression. These data demonstrated, for the first time, that an excess of obtainable iron caused by disordered IL-10 and IL-22 was involved in the pathogenesis of some HAPC patients. The potential benefits of iron removal and immunoregulation for the prevention and treatment of HAPC deserve further research.
Hypobaric hypoxia is the primary cause of high altitude polycythemia (HAPC). Mitochondria are critical organelles that consume high levels of oxygen and generate ATP. We hypothesize that the mitochondrion may be at the center of HAPC, and mitochondrial DNA (mtDNA) SNPs may be involved in its development. First, we conducted a case-control study to investigate the association of mtDNA variants with HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau. Pearson's chi-square tests revealed that mtDNA 8414T (MU) frequency (19.5%) in the HAPC group was significantly higher than that of the control (13.0%, P = 0.04, OR = 1.615, 95% CI: 1.020-2.555). The multivariate logistic regression analysis, after adjustment for environmental factors, revealed that mtDNA 10609T (WT) was significantly associated with an increased risk of HAPC (P<0.01, OR = 2.558, 95% CI: 1.250-5.236). Second, to verify the association, in vitro experiments of transmitochondrial cybrids was performed and revealed that the mtDNA 10609 variant promoted hypoxia-induced increase of intracellular ROS, but the mtDNA 8414 variant did not. Our findings provide evidence that, in Han Chinese, mtDNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a HAPC risk factor.
Seabuckthorn (Hippophae rhamnoides L.) has been used to treat high altitude diseases. The effects of five-week treatment with total flavonoids of seabuckthorn (35, 70, 140 mg/kg, ig) on cobalt chloride (5.5 mg/kg, ip)- and hypobaric chamber (simulating 5,000 m)-induced high-altitude polycythemia in rats were measured. Total flavonoids decreased red blood cell number, hemoglobin, hematocrit, mean corpuscular hemoglobin levels, span of red blood cell electrophoretic mobility, aggregation index of red blood cell, plasma viscosity, whole blood viscosity, and increased deformation index of red blood cell, erythropoietin level in serum. Total flavonoids increased pH, pO(2), Sp(O2), pCO(2) levels in arterial blood, and increased Na+, HCO3-, Cl-, but decreased K+ concentrations. Total flavonoids increased mean arterial pressure, left ventricular systolic pressure, end-diastolic pressure, maximal rate of rise and decrease, decreased heart rate and protected right ventricle morphology. Changes in hemodynamic, hematologic parameters, and erythropoietin content suggest that administration of total flavonoids from seabuckthorn may be useful in the prevention of high altitude polycythaemia in rats.
Objective.-To test the hypothesis that the polymorphisms in the EPAS1 gene are associated with the susceptibility to high altitude polycythemia (HAPC) in Tibetans at the Qinghai-Tibetan Plateau. Methods.-We enrolled 63 Tibetan HAPC patients and 131 matched healthy Tibetans as a control group, from the Yushu area in Qinghai where the altitude is greater than 3500 m. Eight single-nucleotide polymorphisms (SNPs) of the EPAS1 gene, including rs12619696, rs13420857, rs2881504, rs4953388, rs13419896, rs4953354, rs10187368, and rs7587138, were genotyped by the Sequenom MassARRAY SNP assay. Results.-The frequencies of the G allele of EPAS1 SNP rs13419896 were significantly higher in the HAPC group than in the control group (P < .05). Moreover, the A alleles of rs12619696 and rs4953354 were prevalent in the HAPC group, and their counterpart homozygotes were prevalent in the normal Tibetan group (P < .05). Conclusions.-Compared with normal Tibetans, Tibetans with HAPC are maladapted and have a different haplotype in EPAS1 SNPs rs12619696, rs13419896, and rs4953354.
Objective To test the hypothesis that the polymorphisms in the EPAS1 gene are associated with the susceptibility to high altitude polycythemia (HAPC) in Tibetans at the Qinghai-Tibetan Plateau. Methods We enrolled 63 Tibetan HAPC patients and 131 matched healthy Tibetans as a control group, from the Yushu area in Qinghai where the altitude is greater than 3500 m. Eight single-nucleotide polymorphisms (SNPs) of the EPAS1 gene, including rs12619696, rs13420857, rs2881504, rs4953388, rs13419896, rs4953354, rs10187368, and rs7587138, were genotyped by the Sequenom MassARRAY SNP assay. Results The frequencies of the G allele of EPAS1 SNP rs13419896 were significantly higher in the HAPC group than in the control group ( P < .05). Moreover, the A alleles of rs12619696 and rs4953354 were prevalent in the HAPC group, and their counterpart homozygotes were prevalent in the normal Tibetan group ( P < .05). Conclusions Compared with normal Tibetans, Tibetans with HAPC are maladapted and have a different haplotype in EPAS1 SNPs rs12619696, rs13419896, and rs4953354.